Mirror-Image Packing Provides a Molecular Basis for the Nanomolar Equipotency of Enantiomers of an Experimental Herbicide

DOI: 10.1002/anie.201607185

Authors: Claudine Bisson (University of Sheffield) , K. Linda Britton (University of Sheffield) , Svetlana E. Sedelnikova (University of Sheffield) , H. Fiona Rodgers (University of Sheffield) , Thomas C. Eadsforth (University of Dundee) , Russell C. Viner (Syngenta) , Tim R. Hawkes (Syngenta) , Patrick J. Baker (University of Sheffield) , David W. Rice (University of Sheffield)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Angewandte Chemie International Edition , VOL 55 , PAGES 13485 - 13489

State: Published (Approved)
Published: October 2016
Diamond Proposal Number(s): 7423 , 1218

Abstract: Programs of drug discovery generally exploit one enantiomer of a chiral compound for lead development following the principle that enantiomer recognition is central to biological specificity. However, chiral promiscuity has been identified for a number of enzyme families, which have shown that mirror-image packing can enable opposite enantiomers to be accommodated in an enzyme's active site. Reported here is a series of crystallographic studies of complexes between an enzyme and a potent experimental herbicide whose chiral center forms an essential part of the inhibitor pharmacophore. Initial studies with a racemate at 1.85 Å resolution failed to identify the chirality of the bound inhibitor, however, by extending the resolution to 1.1 Å and by analyzing high-resolution complexes with the enantiopure compounds, we determined that both enantiomers make equivalent pseudosymmetric interactions in the active site, thus mimicking an achiral reaction intermediate.

Journal Keywords: chirality; drug design; enantioselectivity; inhibitors; structural biology

Subject Areas: Chemistry, Biology and Bio-materials, Medicine


Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
Bisson_et_al-2016-Angewandte_Chemie_International_Edition.pdf